Zhou Xiaodong, Tan Filemon K, Xiong Momiao, Arnett Frank C, Feghali-Bostwick Carol A
University of Texas Medical School at Houston, USA.
Arthritis Rheum. 2005 Oct;52(10):3305-14. doi: 10.1002/art.21355.
Fewer than 5% of monozygotic (MZ) and dizygotic (DZ) twin pairs are clinically concordant for systemic sclerosis (SSc), yet the majority of MZ twins are concordant for antinuclear antibodies. To discover genetic versus nongenetic molecular pathways important to the pathogenesis of SSc, we compared global gene expression patterns in twins discordant for SSc.
Total RNA from dermal fibroblasts of 15 discordant twin pairs (10 MZ and 5 DZ) and 5 normal controls were used in microarray analysis. Aberrantly expressed genes were confirmed using quantitative real-time reverse transcriptase-polymerase chain reaction.
Lesional and nonlesional fibroblasts from SSc patients showed no significant differences in gene expression, while SSc patients had gene profiles that were significantly different from those of unaffected DZ twins and normal controls. Unaffected MZ twins, however, were not significantly different from SSc patients. Unsupervised hierarchical clustering segregated the fibroblast samples as originating from 2 major groups. Group A contained 5 discordant MZ twin pairs, 3 affected MZ twins, and 3 affected DZ twins. Group B contained all 5 normal population controls, all 5 healthy DZ twins, 2 discordant MZ twins, and 2 discordant DZ twin pairs. Normal fibroblasts incubated with serum from an SSc-affected patient or with serum from her unaffected MZ twin sister developed the increased expression of COL1A2, SPARC, and CTGF typically seen in SSc fibroblasts.
These results demonstrate that dermal fibroblasts from SSc patients and from 40-50% of their genetically identical but clinically unaffected MZ twins exhibit a similar gene expression pattern which can be induced in normal fibroblasts by sera from both. Thus, a stronger genetic predisposition to SSc (than can be detected clinically) is apparent at the molecular level in skin fibroblasts.
单卵双胎（MZ）和双卵双胎（DZ）中临床诊断为系统性硬化症（SSc）的双胞胎对少于5%，然而大多数MZ双胞胎的抗核抗体是一致的。为了发现对SSc发病机制重要的遗传和非遗传分子途径，我们比较了SSc不一致的双胞胎的全基因组表达模式。
15对不一致的双胞胎对（10对MZ和5对DZ）以及5名正常对照的皮肤成纤维细胞的总RNA用于微阵列分析。使用定量实时逆转录聚合酶链反应确认异常表达的基因。
SSc患者的病变和非病变成纤维细胞在基因表达上无显著差异，而SSc患者的基因谱与未受影响的DZ双胞胎和正常对照有显著差异。然而，未受影响的MZ双胞胎与SSc患者无显著差异。无监督层次聚类将成纤维细胞样本分为两个主要组。A组包含5对不一致的MZ双胞胎对、3名受影响的MZ双胞胎和3名受影响的DZ双胞胎。B组包含所有5名正常人群对照、所有5名健康DZ双胞胎中的5名、2对不一致的MZ双胞胎和2对不一致的DZ双胞胎对。用SSc患者血清或其未受影响的MZ双胞胎姐妹血清孵育的正常成纤维细胞，COL1A2、SPARC和CTGF的表达增加，这是SSc成纤维细胞中常见的现象。
这些结果表明，SSc患者及其40%-50%基因相同但临床未受影响的MZ双胞胎的皮肤成纤维细胞表现出相似的基因表达模式，两者的血清均可在正常成纤维细胞中诱导这种模式。因此，在皮肤成纤维细胞的分子水平上，SSc的遗传易感性（比临床检测到的更强）是明显的。
